# Exogenous Epstein–Barr virus nuclear antigen 1 induces ADAR1-driven tumor resistance against immunotherapy

## TL;DR

This study shows how a virus protein, EBNA1, helps tumors resist immunotherapy by boosting RNA editing, and targeting EBNA1 could make tumors more responsive to treatment.

## Contribution

The study reveals a novel mechanism by which EBNA1 exploits ADAR1 to suppress immune responses and suggests targeting EBNA1 as a strategy to improve immunotherapy outcomes.

## Key findings

- EBNA1 overexpression reduces CD8+ T-cell infiltration and inhibits IFN responses in tumor models.
- EBNA1 forms a complex with IGF2BP3 and EIF4G1 to enhance ADAR1 translation and RNA editing.
- Combining EBNA1-targeting PROTAC with anti-PD-1 therapy restores IFN signaling and suppresses tumor growth in mice.

## Abstract

Immune checkpoint blockade (ICB) therapy continues to face limitations due to tumor resistance linked to suppressed interferon (IFN) signaling. This suppression can be attributed to multiple mechanisms, among which viral pathogens represent a compelling though not yet fully elucidated factor. Here, we demonstrate that exogenous Epstein–Barr virus-encoded EBNA1 drives immunosuppression via enhanced RNA-editing enzyme ADAR1-mediated RNA editing. Comparative tumor model analyses revealed that EBNA1 overexpression reduced CD8+ T-cell infiltration, inhibited IFN responses, polarized macrophages toward the M2 phenotype, and accelerated tumor growth. Mechanistically, EBNA1 forms a trimeric complex with insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and eukaryotic translation initiation factor 4G1 (EIF4G1), enhancing ADAR1 translation. Elevated ADAR1 further increased A-to-I editing of dsRNA, particularly within SINE elements near IFN-associated genes. This editing masked immunostimulatory signals, impairing RNA sensor activation and blunting IFN pathways. Notably, combining the EBNA1-targeting PROTAC degrader EP-1215 with anti-PD-1 effectively restored IFN signaling, enhanced T-cell infiltration, and suppressed EBNA1+ tumors in humanized mice. This viral exploitation of RNA editing suggests that targeting EBNA1 could be a strategy to convert “cold” tumors into “hot” targets amenable to ICB therapy.